The present invention relates to microfluidic devices and the control of fluid flow within those devices.
There has been a growing interest in the manufacture and use of microfluidic systems for acquiring chemical and biological information. In particular, when conducted in microfluidic volumes, complicated biochemical reactions may be carried out using very small volumes of liquid. Among other benefits, microfluidic systems increase the response time of reactions, minimize sample volume, and lower reagent consumption. When volatile or hazardous materials are used or generated, performing reactions in microfluidic volumes also enhances safety and reduces disposal quantities.
Traditionally, microfluidic systems have been constructed in a planar fashion using techniques borrowed from the silicon fabrication industry. Representative systems are described, for example, in some early work by Manz et al (Trends in Anal. Chem. (1990) 10(5): 144-149; Advances in Chromatography (1993) 33: 1-66). These publications describe the construction of microfluidic devices using photolithography to define channels on silicon or glass substrates and etching techniques to remove material from the substrate to form the channels. A cover plate is bonded to the top of the device to provide closure.
More recently, a number of methods have been developed that allow microfluidic devices to be constructed from plastic, silicone or other polymeric materials. In one such method, a negative mold is first constructed, and then plastic or silicone is poured into or over the mold. The mold can be constructed using a silicon wafer (see, e.g., Duffy et al., Analytical Chemistry (1998) 70: 4974-4984; McCormick et al, Analytical Chemistry (1997) 69: 2626-2630), or by building a traditional injection molding cavity for plastic devices. Some molding facilities have developed techniques to construct extremely small molds. Components constructed using a LIGA technique have been developed at the Karolsruhe Nuclear Research center in Germany (see, e.g., Schomburg et al, Journal of Micromechanical Microengineering (1994) 4: 186-191), and commercialized by MicroParts (Dortmund, Germany). Jenoptik (Jena, Germany) also uses LIGA and a hot-embossing technique. Imprinting methods in polymethylmethacrylate (PMMA) have also been demonstrated (see, e.g., Martynova et al., Analytical Chemistry (1997) 69: 4783-4789). However, these techniques do not lend themselves to rapid prototyping and manufacturing flexibility. Moreover, the tool-up costs for such techniques are quite high and can be cost-prohibitive.
Typically, flow control within microfluidic devices has been provided through the application of electric currents to cause electrokinetic flow. Systems for providing such utility are complicated and require electrical contacts to be present. Additionally, such systems only function with charged fluids, or fluids containing electrolytes. Finally, these systems require voltages that are sufficiently high as to cause electrolysis of water, thus forming bubbles that complicate the collection of samples without destroying them. Therefore, there exists a need for a microfluidic device capable of controlling flow of a wide variety of fluids without using electrical currents.
Some of the basic challenges involved in operating microfluidic systems result from attempts to interface between conventional xe2x80x9cmacro-scalexe2x80x9d devices and microfluidic components. Due to the very small cross-sectional area of microfluidic channels, flow through these channels can be quite sensitive to pressure variations. Assuming that an external pressure source is used to motivate fluid flow in a microfluidic system, a number of applications would benefit if the flow rate of a flowing fluid could be controlled in spite of variations in input pressure. For example, such control can be especially valuable in performing reactions such as chemical or biological synthesis. To reduce overall costs and provide versatility, it would be desirable to achieve controlled fluid flow within a microfluidic device using various low-precision pressure sources, such as, for example, a conventional manually-operated syringe or an inexpensive, low-precision syringe pump. Also in the interest of reducing costs, it would be desirable to provide controlled fluid flow in a microfluidic device with a minimum of moving parts or control components. Thus, there exists a need for a simple yet robust microfluidic regulating device capable of receiving fluid from a low-precision source and providing a controlled fluid flow rate in spite of fluctuations in input pressure.
A microfluidic device with limited (i.e., on-off) flow control capability is provided in U.S. Pat. No. 5,932,799 to Moles (xe2x80x9cthe Moles ""799 patentxe2x80x9d). There, polyimide layers enhanced with tin (between 400-10,000 ppm) are surface micromachined (e.g., etched) to form recessed channel structures, stacked together, and then thermally bonded without the use of adhesives. A thin, flexible valve member actuated by selective application of positively or negatively pressurized fluid selectively enables or disables communication between an inlet and an outlet channel. The valve structure disclosed in the Moles ""799 patent suffers from numerous drawbacks that limit its utility, however. First, the valve is limited to simple on-off operation requiring a constant actuation signal, and is incapable of regulating a constant flow. Second, the valve is normally closed in its unactuated state. It is often desirable in microfluidic systems to provide normally open valve structures subject to closure upon actuation. Third, the Moles ""799 patent teaches the fabrication of channels using time-consuming surface micromachining techniques, specifically photolithography coupled with etching techniques. Such time-consuming methods not only require high setup costs but also limit the ability to generate, modify, and optimize new designs. Fourth, the Moles ""799 patent teaches only fabrication of devices using tin-enhanced polyimide materials, which limits their utility in several desirable applications. For example, polyimides are susceptible to hydrolysis when subjected to alkaline solvents, which are advantageously used in applications such as chemical synthesis. The inclusion of tin in the device layers may present other fluid compatibility problems. Finally, polyimides are generally opaque to many useful light spectra, which impedes their use with common detection technologies, and further limits experimental use and quality control verification.
Another microfluidic valve structure having limited utility is disclosed in WIPO International Publication Number WO 99/60397 to Holl, et al. There, a microfluidic channel is bounded from above by a thick, deformable elastic seal having a depressed region that protrudes through an opening above the channel. An actuated external valve pin presses against the elastic seal, which is extruded through the opening into the channel in an attempt to close the channel. This valve, however, suffers from defects that limit its utility. To begin with, it is difficult to fabricate an elastic seal having a depressed region to precisely fit through the opening above the channel without leakage. Additionally, the valve provides limited sealing utility because it is difficult to ensure that the extruded seal completely fills the adjacent channel, particularly in the lower corners of the channel. Further, the contact region between the external valve pin and the elastic seal is subject to frictional wear, thus limiting the precision and operating life of the valve.
Using conventional technologies, it is generally difficult to quickly generate and modify designs for robust microfluidic devices. To include flow control capability in such a device only elevates that difficulty. It would be desirable to provide a xe2x80x9cgenericxe2x80x9d microfluidic platform that could be quickly and easily tuned with various components and/or materials to provide different flow control utilities depending on the particular application, taking into account varying design criteria such as the operating fluid, the flow rates, and the pressures involved. If available, such a platform would promote rapid prototyping and device optimization at a substantially reduced cost compared to conventional technologies.
Additionally, it would be desirable to enable flow through a microfluidic channel network to be externally controlled without the attendant drawbacks of electrokinetic or electrophoretic flow. In particular, it would be desirable to provide a channel network having multiple inlets and multiple outlets, and be able to selectively establish fluid flow paths through the network between one or more specific inlets and one or more specific outlets. If available, such a device could be used as a versatile fluid xe2x80x9cswitch.xe2x80x9d It would be particularly desirable if this fluid switching utility could be externally programmed so as to execute repetitive and/or sequential functions with minimal user interaction. Preferably, a fluid switching device or system would be simple and robust with a minimum number of parts subject to wear.
Finally, conventional xe2x80x9con-offxe2x80x9d microfluidic valve structures such as the valve disclosed in the Moles ""799 reference require constant application of a control signal, thus consuming external actuation resources for as long as a valve state is to be maintained. To reduce the consumption of external actuation resources and provide other capabilities including fluid logic functions, it would be desirable to provide robust microfluidic valves with xe2x80x9clatchingxe2x80x9d capability, in other words, the ability to maintain position in an actuated state without continuous application of an actuation signal. These and other needs and desirable aspects are addressed herein.
In a first separate aspect of the invention, a microfluidic regulating device includes a first channel segment and a second channel segment defined in different layers of a microfluidic device and in fluid communication with one another. A membrane separates the channel segments at a regulatory region. In the presence of a pressure differential between the two channel segments, the membrane is deformed into the channel segment having a lower internal pressure, thus reducing fluid flow capability through the first or the second channel segment.
In another separate aspect of the invention, a multi-layer microfluidic regulating device includes a first channel segment and a second channel segment defined in different layers of a microfluidic device. The second channel segment is in fluid communication with the first channel segment, and a membrane separates the first channel segment and the second channel segment at a regulatory region. When a pressure differential is applied between the first channel segment and the second channel segment, the membrane deforms into and constricts the channel segment having a lower internal pressure.
In another separate aspect of the invention, a microfluidic regulating device includes a first device layer defining a first channel segment through its entire thickness, and a second device layer defining a second device layer through its entire thickness. The second channel segment has an inlet and a regulated outlet, and the first channel segment is in fluid communication with the inlet. A pressure responsive deformable membrane is disposed between at least a portion of the first channel segment and a portion of the second channel segment.
In another separate aspect of the invention, a microfluidic regulating device includes a first device layer defined through its entire thickness and a second device layer defined through its entire thickness. The first layer has an inlet and an outlet, and the second layer has an inlet and two outlets. A third device layer disposed between the first and second layers defines an aperture that permits communication between the first layer outlet and one of the second layer inlets. At least a portion of the first channel overlaps a portion of the second channel to form a regulatory region associated with either of the second layer outlets.
In another aspect of the invention, any of the foregoing separate aspects may be combined for additional advantage.
These and other aspects and advantages of the present invention will become apparent from the following detailed description of the preferred embodiments taken in conjunction with the figures.